Recently much attention has been focused on the need for new antimicrobial agents. Heavy antibiotic use and person-to-person spread of bacteria have greatly increased antibiotic resistant due to genetic mutation, and this problem is continually increasing in severity. The overuse of antibiotics promotes microbial resistant, which can arise from changes in microbial permeability barriers or drug-binding sites, or from the acquisition of enzymes that destroy the antimicrobial agents. The bacterium Pseudomonas aeruginosa is a prime example: 30% of clinical isolates from ICU or nursing home patients are now resistant to 3 or more drugs, and a similar situation exits for other organisms.
New antibacterial agents are also needed because conventional antibiotics generally work poorly in chronic infections, even when the bacteria are susceptible when tested ex vivo. A key factor accounting for this is that the infecting organisms live in biofilms, surface-associated bacterial communities encased in a polymeric matrix. An alginate film frequently surrounds the bacteria in the biofilm state. Physiological changes inherent to biofilm growth make bacteria far more resistant to killing by the immune system and antibiotics than cells in the free-living (planktonic) state. As a consequence of the biofilm lifestyle, bacteria can tolerate exposure to antibiotics and biofilm infections are notoriously difficult to treat and often impossible to cure. Examples of biofilm infections include the airway infections in cystic fibrosis (CF) patients, chronic wound, and sinus infections, endocarditis and medical devices, among other.
An approach to circumvent the resistance problem in bacterial infection is to target the transport system of the siderophores for the drug delivery into the bacterial cell. Siderophores (Greek for iron carriers) are iron chelating compounds secreted by microorganisms. The compounds are used by microorganisms to dissolve insoluble Fe(III) ions by chelation as soluble Fe(III) complexes that can be taken up by active transport mechanisms and sequestered through the cell membrane into the periplasmatic space, where the iron is set free by reduction to Fe(II). Siderophores commonly occur in two broad chemical classes, hydroxamate and catechols, one of which occurs with almost every group of bacteria. Hydroxamate siderophores includes, among other, desferrioxamine, ferrichrome, and aerobactin.
Desferrioxamine (DFO) is an iron-specific chelating agent which has been used for the treatment of iron overload since the early 1960s. The antibacterial and antifungal activity of desferrioxamine was evaluated and reported to have limited potential as an antibacterial agent. Lowy, F. D. et al., Antimicrobial Agents and Chemotherapy 25(3):375-376, 1984. In previous studies, it has been shown that systemic treatment with zinc-desferrioxamine (DFO-Zn) and gallium-desferrioxamine (DFO-Ga) reduced damage to the retina subjected to ischemia and reperfusion, in accord with their enhanced infiltrability through the blood-retinal barrier. See Ophir, A. et al., Invest. Opthalmol. Vis. Sci. 35:1212-22, 1994; and Banin, E. et al., Free Radic. Biol. Med. 28:315-23, 2000. Likewise, topical application of DFO-Zn reduced corneal damage following alkali burn. See Siganos, C. et al., Cornea 17:191-50, 1998. In addition, it has been reported that the gallium-desferrioxamine is useful in the treatment of free radical-induced pathological conditions; the treatment of injury resulting from ischemic insult to the heart, brain, or kidney; the treatment of thalassemia; the treatment of hemochromatosis; the treatment of Wilson's disease; the treatment of paraguate toxicity; or for exchanging gallium for iron. See U.S. Pat. No. 5,618,838 issued to Chevion et al. Several siderophore-antibiotic conjugates have been developed to be used as antibacterial agents. Budzikiewicz, H. Current Topics in Medicinal Chemistry 1:73-83, 2001. However, these conjugates have not produced promising results in controlling or eradicating biofilm formation.
Therefore, there is a need for an antibacterial agent that is effective against drug resistant bacterial infection and biofilm-forming bacteria. The present invention seeks to fulfill these needs and provides further related advantages.